We propose to therapeutically exploit Schistosoma haematobium-derived IPSE (Interleukin-4 inducing Principle from Schistosoma mansoni Eggs) to mitigate bladder hypersensitivity. The incidence of bladder hypersensitivity (i.e., interstitial cystitis/bladder pain syndromes and overactive bladder) in some patient populations is over 40%, and existing treatments are ineffective for many. Thus, novel therapeutics are needed. The S. mansoni homolog of IPSE (M-IPSE) alters host biology by three distinct mechanisms: 1) translocating into nuclei of target cells to alter gene transcription; 2) binding IgE on basophils and mast cells to trigger IL-4 secretion; and 3) sequestering chemokines. We have shown that the S. haematobium homolog of IPSE (H-IPSE) translocates into urothelial cell nuclei and binds IgE on basophils. Our in silico data show H- IPSE binds CCL2. Collectively, these findings illustrate that H-IPSE and M-IPSE share many host modulatory features, but their differences are unclear. Immune and non-immune modulation of the bladder may be a new management approach for bladder hypersensitivity. Blocking CCL2-CCR2 interactions in bladder nerves and dorsal root ganglia lowers pain in rodent models. IL-4 lessens ifosfamide-induced cystitis in mice and decreases bladder pain and overactivity. Yet, intravenous IL-4 has adverse side effects in patients. We have discovered that a single intravenous dose of H-IPSE is superior to both Mesna and recombinant IL-4 in suppressing ifosfamide-induced bladder hemorrhage, and that it reduces urinary frequency and pain behaviors through IL-4- and nuclear localization sequence-dependent mechanisms. In conclusion, a single dose of H- IPSE lessens bladder hypersensitivity in two mouse models through pathways consistent with the known properties of M-IPSE and H-IPSE. We hypothesize that H-IPSE and M-IPSE variants can be optimized as safe therapeutics for bladder hypersensitivity by defining and exploiting their nuclear localization signal-, IL-4-, and chemokine binding-reliant mechanisms. To test this hypothesis, we will, in Aim 1, define and optimize the mechanisms by which IPSE exerts therapeutic effects in bladder hypersensitivity through the generation of engineered mutants with: 1) greater nuclear translocation ability to which will dampen transcription of pain- related genes; 2) increased capacity to induce IL-4 production; and 3) enhanced sequestration of chemokines.
In Aim 2, we will determine the chronic toxicity potential of IPSE. We hypothesize that H-IPSE and M-IPSE variants and mutants that induce apoptosis of intestinal epithelial cells or dendritic cells upon nuclear translocation will cause toxicity when given on a chronic basis. Finally, we theorize that IPSE variants/mutants which do not trigger cancer gene-related transcription upon nuclear translocation into urothelial cells will not cause bladder cancer. Our work is unique in that it demonstrates that a uropathogen-derived host modulatory molecule can be therapeutically exploited in bladder disease models. The completion of these studies will yield a better understanding of the multiple immune and non-immune aspects of bladder hypersensitivity and potentially identify therapeutic candidates for this constellation of symptoms.

Public Health Relevance

Painful bladder syndromes affect up to 40% of some patient populations and effective therapies do not exist for many of these people. We propose to exploit a parasite-derived protein, IPSE, as a candidate therapeutic due to its ability to modulate host immune and non-immune responses to bladder injury. We hypothesize that IPSE can be optimized for therapeutic potential (while minimizing toxicity) through the generation of mutant forms with altered ability to modulate host responses via three distinct mechanisms: IL-4-binding, chemokine-binding, and nuclear localization.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Bavendam, Tamara G
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Children's Research Institute
United States
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Mbanefo, Evaristus C; Le, Loc; Pennington, Luke F et al. (2018) Therapeutic exploitation of IPSE, a urogenital parasite-derived host modulatory protein, for chemotherapy-induced hemorrhagic cystitis. FASEB J 32:4408-4419
Gerber, Daniel; Forster, Catherine S; Hsieh, Michael (2018) The Role of the Genitourinary Microbiome in Pediatric Urology: a Review. Curr Urol Rep 19:13
Ishida, Kenji; Hsieh, Michael H (2018) Understanding Urogenital Schistosomiasis-Related Bladder Cancer: An Update. Front Med (Lausanne) 5:223
Pennington, Luke F; Alouffi, Abdulaziz; Mbanefo, Evaristus C et al. (2017) H-IPSE is a pathogen-secreted host nucleus infiltrating protein (infiltrin) expressed exclusively by the Schistosoma haematobium egg stage. Infect Immun :